Cachexia-anorexia syndrome is a life-threatening aspect to many diseases, in particular many forms of cancer or therapies for cancer. The obvious symptoms of this disease include lack of appetite, and a loss of lean body mass disproportionate to the reduction in caloric intake. However, the less obvious effects include multi-organ failure, due to high metabolic rate-induced apoptosis. The economic costs of cachexia are huge. The National Cancer Institute estimates that up to 40% of cancer deaths are directly due to cachexia, and it is likely a factor in a significant percent of other cancer fataliies. Hyperactivity of the central melanocortin (MC) system appears to be a common factor in most, if not all, forms of cachexia. In addition, recent evidence indicates that the lethargy (lack of activity/movement) associated with cachexia inducing diseases is not MC system mediated, but rather due to suppression to the central orexin system. Thus, the ideal anti-cachectic drug would combine the properties of a MC antagonist and orexin system agonist or stimulator. Analysis of MCR ligands with in vivo assays, demonstrated the dissociation of MC from cardiovascular (C-V) activity, suggesting a solution to the long-standing problem of MC C-V side-effects Our Phase 1 Proof of Concept was to produce derivatives of MC peptide antagonists that chronically suppressed C-V activity, while maintaining anti-anorexic activity. Phase 1 of this project was highly successful. We first made a detailed investigation of MC C-V actions, using arterial pressure, heart rate, and the electrocardiogram. MC ligand C-V activities replicate actions associated with RFamide peptides in different experimental models. The direct cardiac effects modeled the clinical symptoms of sick sinus syndrome and sudden cardiac arrest. Thus, the endogenous RFamide system may have an etiological role in these human cardiac disorders. We then designed and synthesized MC cyclic peptide antagonists with an enzymatically stable C-terminal extension. This compound had no C-V activity, lacked the dose-limiting behavioral side-effects associated with other anti-cachectic MC antagonists, produced a 100% reversal of cachexia in an aggressive experimental cancer model, and suppressed cachexia-induced lethargy. Our Phase 2 Specific Aims are 1) design a MC antagonist peptide to maximize oral absorption and blood brain barrier transport; 2) determine therapeutic index and pharmacokinetics in experimental models, and 3) confirm the anti-cachexia-anorexia effects in canine malignancies. Tensive Controls will complete the work necessary to develop anti-cachexia therapeutic, and move it into formal pre-clinical development. This will produce an anti-cachexia drug that will increase the treatment window for malignancies.